Elucidation of pathological mechanism caused by defects in the repair of TOPII-induced DNA double-strand breaks

2018 Fiscal Year Final Research Report

• Project/Area Number: 16H02953
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: Kyoto University
• Principal Investigator: SASANUMA Hiroyuki 京都大学, 医学研究科, 准教授 (00531691)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: ゲノム / ゲノム編集 / 相同組換え / DNA損傷修復 / DNA二重鎖切断 / ステロイドホルモン / トポイソメラーゼ2

Outline of Final Research Achievements

The aim of this study is to characterize the DNA damages induced by estrogen and clarify the molecular mechanism of how estrogen-induced DNA damages are repaired. To this end, we generated BRCA1 and TOP2b deficient cells using breast cancer MCF-7 cells. We found that estrogen induced Top2b; covalently bound to DSB ends, named TOP2cc, in serum starved G1-phase cells. The loss of BRCA1 caused the accumulation of TOP2cc induced by estrogen, indicating an important role of BRCA1 in the repair of estrogen-induced DSBs. We have previously demonstrated that MRE11 nuclease also functions in the removal of Top2cc from DSB ends. BRCA1 promotes the recruitment of MRE11 onto Top2cc sites for subsequent removal of Top2cc. Our results suggest the loss of BRCA1 enhances estrogen’s genotoxicity. This function of BRCA1 may help explain the female organ-specific carcinogenesis of BRCA1-mutation carriers.

Free Research Field

放射線生物学

Academic Significance and Societal Importance of the Research Achievements

家族性乳がん卵巣がん症候群は、30代ぐらいから発がん率が上昇します。BRCA変異がなぜ女性臓器特異的がんを発症するかはわかっていませんでした。エストロゲンは、細胞増殖促進作用があることは知られていましたが、DNAを傷つける毒性については知られていませんでした。本研究では、BRCA1が欠損することによってエストロゲンのDNA毒性が増強し、発がんに繋がることを明らかにしました。